Endometriosis – a painful disease

Purpose of review This review looks to overview advances in endometriosis-associated pain, both in understanding the pain mechanisms involved and increasing treatment options with well designed clinical trials and meta-analyses. Recent findings Our understanding of endometriosis-associated pain has progressed from a purely nociceptive model to an awareness that both neuropathic and nociplastic mechanisms can be present for some people with endometriosis. Clinical trials and meta-analyses have demonstrated efficacy of surgical treatments and hormonal therapies. It is notable that currently, the basic science and clinical trials are not cross-fertilising. Summary Following growth in other areas of chronic pain, there have been significant advances in our understanding of endometriosis-associated pain. However, there remains lots to explore and we are currently a long way from our goal of timely personalized holistic multidisciplinary treatment for all sufferers of endometriosis-associated pain.


INTRODUCTION
Endometriosis is defined as the presence of tissue resembling the endometrium outside of the uterus and affects one in 10 women of reproductive age, and an unknown number of trans-men, nonbinary and sex diverse people [1]. It is important to be aware that symptoms often start in adolescence and may not stop after reproductive age, continuing beyond the menopause for some. Endometriosis is a painful disease for many. It is often associated with chronic pelvic pain; however, not everyone with the condition experiences pain and those that do have endometriosis-associated pain (EAP) are incredibly heterogeneous in their presentations [2]. Furthermore, the stage or extent of the endometriosis visualized during surgery does not correlate with pain symptoms [2]. These features make it a challenging condition to treat clinically and to research.
Although endometriosis has long been the primary diagnosis considered by Gynaecologists when a woman presents with pelvic pain, until relatively recently, there was little public awareness and limited research funding allocated to the condition (despite the fact that it is as common as asthma and diabetes) [3][4][5]. EAP was particularly poorly researched. Over recent years, however, there has been an increasing interest in this area with robust studies published in pain as well as gynaecology journals. Figure 1 shows the number of articles published in 15 of the top pain journals over the past 15 years that contain 'endometriosis' and clearly illustrates the increase very recently. Here, we aim to review this recent literature, highlighting the articles we consider most important in moving our understanding of this debilitating clinical condition forwards. It is beyond the scope of this review to comprehensively cover both clinical and preclinical research advances, and therefore, we will limit our discussion to clinical research. However, we wish to acknowledge the importance of preclinical research in advancing our understanding and highlight that although there have been important advances, pain still remains poorly assessed in preclinical models of endometriosis [6,7]. experienced. These can be spontaneous or evoked and the mechanisms generating and maintaining these pains may differ (Table 1) [8].
These pains may not be present every day and assessment tools need to be able to capture this variation and (particularly when used as outcome measures in clinical trials) account for changes in the frequency of provoking factors. For example, many hormonal treatments for endometriosis will alter the menstrual cycle including inducing amenorrhoea, and the frequency of sexual activity can vary over time and may not be related to disease activity. Moreover, there is increasing awareness of comorbid chronic pain conditions and endometriosis is commonly associated with other pelvic pain conditions such as irritable bowel syndrome (IBS), interstitial cystitis/bladder pain syndrome (IC/BPS) and vulval pain syndromes as well as nonpelvic pains such as migraine and fibromyalgia [9,10 && ,11]. Distinguishing which pain symptoms are due to the endometriosis specifically is challenging and it is important to capture the full pain burden experienced. A number of recent studies have highlighted that those with endometriosis and other pain syndromes are particularly impacted by their pain [9,11,12 & ,13 && ], and this is an area that clearly warrants further study.
Although historically EAP has been considered nociceptive, with research focussing primarily on

KEY POINTS
Endometriosis-associated pain is complex and the mechanisms underlying it are likely multifactorial.
Recent advances in the understanding of endometriosisassociated pain have highlighted the importance of considering nociplastic and neuropathic pain mechanisms.
More work needs to be done to ensure clinical trials carried out evaluate all aspects of pain appropriately.
Stratification of people with endometriosis-associated pain has high potential for understanding mechanisms and moving towards personalized clinical management. the endometriosis lesions as the pain generator (in particular inflammation and fibrosis) [8], more recent work has been informed by other chronic pain conditions and begun to investigate both neuropathic and nociplastic mechanisms in this population. There are multiple reasons why a neuropathic component may be present in some people with EAP: most people with endometriosis will have undergone at least one surgical procedure for diagnosis and/or treatment; endometriotic lesions are innervated and these new nerve fibres are exposed to an inflammatory pelvic environment; nerve fibres can be damaged by the burning/cutting undertaken during surgical treatment of the disease. Using the painDETECT questionnaire as a screening tool, we found 40% of respondents to an online survey had features of neuropathic pain [14]. This included reports of typical clinical signs of neuropathic pain such as numbness and mechanical hyperalgesia. Using quantitative sensory testing (QST), we subsequently showed that in EAP, both gain of function (such as hyperalgesia) and loss of function (similar to numbness) are seen [15 & ]. Further investigation in this area is urgently needed, not least because our current recommended medical management options for EAP are limited to hormone therapies and simple analgesics. To date, no medications targeting a neuropathic component to pain have been trialled in EAP specifically. Although gabapentin was shown to be no better than placebo in a recent adequately powered randomized controlled trial (RCT) in women with chronic pelvic pain without identified underlying disease [16], it is plausible that its effect may be different in those with endometriosis.
A number of novel tools and approaches have been utilized to investigate the experience of the relatively newly defined nociplastic pain in endometriosis, and this is the pain mechanism, which has perhaps seen the greatest expansion in research. Recent studies have used questionnaire measures in people with EAP as a pragmatic approach to evaluate the presence and associations of nociplastic pain and its impact on response to surgical treatment. ]. Moreover, higher scores on these measures were associated with a higher likelihood of persistent pain postsurgical treatment (both conservative surgery and hysterectomy) and a greater intensity of these pains [13 The studies described here and others highlight the complexity of the underlying pain mechanisms in EAP and the need for a variety of different measures to fully capture this experience. There has been much work on standardized assessment tools and core outcome sets over recent years; however, to date, the 'perfect' set does not exist. The World Endometriosis Research Foundation Endometriosis Phenome and Biobanking Harmonization Project (WERF EPHect, https://endometriosisfoundation. org/ephect/) has produced SOPs, questionnaires and forms for research projects including a clinical covariates questionnaire, and we are aware that work on a clinical examination tool is ongoing. Although these have been hugely valuable in aligning research around the world and have formed the basis of a number of large-scale collaborative projects that would not otherwise have been possible, they are long and relatively burdensome for participants to complete and thus cannot be used for clinical trials or studies wherein assessments at multiple time points are needed. Moreover, currently, they do not include measures allowing the differentiation of nociceptive, neuropathic and nociplastic pain, given how we now understand the value of these it will be important to update these tools to include such measures. A core outcome set for clinical trials has been recommended [20]; however, this has a relatively limited focus on pain and does not even capture all domains recommended by IMMPACT [21], let alone those discussed above. If this is adopted widely for clinical trials in EAP, we hope that researchers will expand it with these additional tools. Given that the mainstay of diagnosis and treatment of endometriosis remains surgical, it is important that appropriate pain measures are not only captured in clinical trials of surgical treatments but also that we consider the very real possibility of postsurgical pain. Recent work has taken a wide variety of stakeholder opinions to generate a core outcome set for acute postsurgical pain and this includes surgery related to endometriosis [22]. We look forward to seeing similar recommendations for chronic postsurgical pain.
Currently available assessment tools do not allow us to determine the cause of pain; however, recent genome-wide association studies (GWAS) ]. Importantly, they were also able to demonstrate a genetic basis to the comorbidity with other pain conditions, such as migraine, back and multisite chronic pain and osteoarthritis [9,11].

SURGICAL AND PHARMACOLOGICAL CLINICAL TRIALS
The James Lind Alliance priority setting partnership in endometriosis highlighted the importance to both patients and clinicians of new treatment options for EAP [24]. There have been increasing numbers of clinical trials in endometriosis published and we are aware of a number of well designed trials currently running around the world. Disappointingly, however, the majority of these trials focus on treatment of the endometriosis lesion by surgical or medical approaches, rather than considering EAP as a chronic pain condition.
Whilst there is no noninvasive diagnostic test for endometriosis, surgery remains a key part of the diagnostic pathway, being needed to definitively rule out endometriosis [25]. As most guidelines now advocate a 'see and treat' approach rather than undertaking separate diagnostic and then therapeutic procedures, it is essential that we better understand the impact of surgery on EAP. Towards this aim, a recent meta-analysis looked at pain outcomes for excision compared with ablation surgery, finding no significant difference between these two methods [26]. Importantly, they highlighted the need for larger randomized control trials with longer follow-up to better determine the true effect. One trial currently running [27] seeks to determine whether there is benefit of surgically treating superficial peritoneal endometriosis at all. Although we are aware that there has been controversy regarding this trial, we consider it essential to understand the benefit of what is an incredibly common surgical procedure that was brought into routine clinical practice with little evidence supporting its efficacy. Although cross-sectional studies tell us nothing about cause and effect, we did identify a relationship between increasing numbers of surgical procedures and rates of neuropathic pain in people with endometriosis [14], and therefore, further work is also needed to assess the benefit (or harm) of repeated surgical procedures for endometriosis.
An important study was recently published that investigated which women with chronic pelvic pain would undergo surgery and in whom endometriosis was found [28

&&
]. It showed that predictors of surgery included gynaecology unit, lower parity and more severe pain, but there were no predictors of endometriosis presence at surgery. This important study holds a mirror up to research in endometriosis and how the need for a surgical diagnosis to enter research studies results in some unknown preselection bias.
Current guidance recommends hormonal therapies as an alternative approach to surgery for EAP. There are already many trials exploring the use of a variety of hormonal preparations for this indication, albeit mostly poorly assessing pain and not aligning with IMMPACT recommendations for chronic pain trials [21]. Recently published meta-analyses have demonstrated the efficacy of both GnRH antagonists [29] and progestins on pain outcomes [30]. However, not all the included studies assess the different types of pelvic pain associated with endometriosis, and importantly, these therapies frequently induce amenorrhoea and this is often not well accounted for in the analysis. Considering all medical treatments, a network meta-analysis found that GnRH analogues, progesterone and elagolix (a GnRH antagonist) were the highest-ranked medical treatments for EAP [31 && ]. Interestingly, their analysis did not support the use of NSAIDs, a treatment whose use is widespread and recommended in current guidelines.

MULTIDISCIPLINARY CARE
It is increasingly recognized that a multidisciplinary approach to management is optimal for chronic pain, with medication, surgery and other interventional procedures used in combination with physical and psychological therapies. Despite the increasing body of evidence demonstrating similarities between EAP and other chronic pain conditions, relatively few studies have considered these types of therapies either alone or as a component of a multidisciplinary pain management programme. This is disappointing given that there is evidence of benefit in chronic pelvic pain more generally [1,32].
A systematic review of pain-focused psychological interventions highlighted that, although studies were of mixed quality, they generally supported the effectiveness of such interventions for improving the lives of those living with EAP [33]. Mindfulness-based interventions have received the most attention, which contrasts with chronic pain conditions more broadly, wherein cognitive behavioural therapy has been more commonly used. This likely reflects research trends in the field of psychology, wherein interest in mindfulness-based interventions and EAP research have developed in parallel. More recently, Moreira et al. [34 & ] explored whether a mindfulnessbased intervention provided additional benefits to surgery. This reflects an important position: what can psychological therapies add to existing management strategies? So often, these approaches are conceptualized as alternatives, reflecting out-dated mind-body dualism.
Despite evidence of the importance of a musculoskeletal component to EAP [19,35 && ,36], there is limited literature exploring the efficacy of physiotherapy in EAP. It will be essential to address this if evidence-based multidisciplinary treatment regimes are to be designed. In addition, although dietary approaches are quite commonly recommended for EAP, there is little evidence to support these. Interestingly, a recent systematic review of the effects of vitamin D supplementation in endometriosis found that whilst in animal and in-vitro trials, there was a regression in lesions, this did not translate to a reduction in pain scores in clinical studies [37]. It will be interesting to see how other supplements, similarly, informed by robust basic science, translate to clinical effect (e.g. [38]).

FUTURE WORK
Although there has been significant progress in EAP research, there remains much that is not well understood. It is clear from the studies discussed above that a personalized medicine approach to EAP will be essential to reduce the time to successful treatment and the harm associated with unsuccessful therapeutic approaches. Although some recent studies have stratified/excluded participants on the basis of stage of endometriosis [39][40][41][42][43] or BMI [44], to date, no studies have stratified on the basis of pain characteristics. Questionnaire measures and potentially psychophysical assessments may help to identify underlying pain mechanisms and thus inform clinical trial design [45].
There is also increasing interest both from researchers and general public in 'femtech' broadly and how it can be applied to endometriosis. However, it is important for such advances to be tested thoroughly, with rigorous clinical trials with appropriate placebo controls [46 & ]. When new technologies are developed and marketed without full clinical trials, a rift is created between consumer healthcare markets and clinical guidelines [43,47].
It is essential that future research improves its diversity. Current research cohorts do not well reflect the clinical population in which they are hoping to have impact. We are aware of new cohorts being set up in under-researched regions [48][49][50][51][52][53], but it is increasingly clear that there are systemic disparities in access to care throughout the developed world [54]. Thus, continuing to focus our research efforts only on those with a surgical diagnosis will perpetuate these biases. Importantly, most women will first present in community/primary care settings and a large proportion of their ongoing care will also be delivered here. It is clear that primary care physicians also have many unanswered questions about optimum management, which future studies must address [55 & ].
In addition to such research, endometriosis needs to be de-stigmatised in order to remove barriers to general awareness, care and research. For this, better education around menstrual health and what is 'normal' is vital. The impact of lack of knowledge of what is normal hugely impacts healthcare seeking and care received [56] and general lack of societal acceptance leads to loss of social connection [57].
Finally, it is worth reflecting on potential differences between research participants in the next few years compared with those from pre2020. The COVID-19 pandemic hugely impacted on access to care for those with endometriosis around the world [58]. Although access to medical therapies returned relatively quickly, the impact on waiting times for surgery continues to be felt, resulting in greater diagnostic delay and a longer duration of pain. We are aware that the pandemic worsened pain scores and associated symptoms for individuals [59,60], but we currently do not know the longterm impacts.

CONCLUSION
Although EAP research is gaining momentum, there remains much to be done. Historically, EAP has been considered solely as a nociceptive 'end-organ' disease and the legacy of this remains. More needs to be done in learning from the field of chronic pain, pulling across both methodology and understanding, which can be applied to this population, which remains under-served both in research and clinics. However, patients and clinicians should feel positive about the advances made in understanding EAP in recent years. We hope that this nuanced understanding of pain on an individual basis will allow clinical practice to move on from a one-size-fits-all approach to a holistic personalized multidisciplinary treatment regime with the potential for greater benefit across all domains of wellbeing and improvements in quality of life for those living with EAP.

Financial support and sponsorship
There was no financial support nor sponsorship for this article.

Conflicts of interest
LC and EE report no conflicts of interest. K.V. reports research funding from NIHR, MRC, NIH, the EU and Bayer Healthcare; and honoraria for presentations and consultancy from Bayer Healthcare, AbbVie, Reckitts and Eli Lilly. In this study, authors identified that those with higher scores on the CSI (a 35-item questionnaire measure) before surgery (both conservative surgery and hysterectomy) had greater noncyclical pelvic pain, deep dyspareunia, dyschezia and back pain intensity at follow up. This demonstrates the need to investigate pain mechanisms underlying pain in planning treatment strategies. This study explores the relationship between nociplastic pain and chronic pelvic pain symptoms using the Fibromyalgia Survey Score. They found that higher levels of nociplastic pain were associated with greater pelvic pain severity, frequency, interference and pelvic myofascial pain, independent of presence of endometriosis, history of surgical procedures, age and BMI.

18.
& As-Sanie S, Till SR, Schrepf AD, et al. Incidence and predictors of persistent pelvic pain following hysterectomy in women with chronic pelvic pain. Am J Obstet Gynecol 2021; 225:568.e1-568.e11. This study described the incidence of persistent pelvic pain in the 6 months following hysterectomy in women with chronic pelvic pain and predictors of it. They found that higher degrees of centralized (or nociplastic) pain prior to hysterectomy was a predictor of persistent pelvic pain after surgery. This highlights the importance of understanding pain mechanisms prior to surgical intervention to determine whether benefit would be expected.  This important prospective observational cohort study (n ¼ 471) explored who received diagnostic laparoscopy and in whom endometriosis was diagnosed. They found that pelvic pain severity did not predict endometriosis diagnosis or staging. In addition, they found that predictors of surgery included gynaecology unit, which is an important consideration given the need for a surgical diagnosis in the inclusion criteria for a lot of endometriosis research and thus unknown bias in cohorts. A meta-analysis of evidence for a range of medical therapy options. They found that progestin medications did reduce pain in endometriosis. Their analysis highlighted the high heterogeneity in the response to progestins, an area which whilst often reported and well established remains poorly understood. Consideration of underlying pain mechanisms or other patient characteristics may therefore be just as important for personalizing medical treatments as it is for surgical approaches.